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Intake of tree nuts is associated with a lower risk of cardiovascular events in prospective cohorts and the PREDIMED (Prevención con Dieta Mediterránea) trial (1). Previous meta-analyses indicated that tree nut intake lowered low-density lipoprotein (LDL) cholesterol (2,3). However, few trials (≤13 studies) were included in these meta-analyses; pooled effects were not standardized to a common dose, which prevented conclusions about the magnitude of effects for a given intake of nuts, and specific constituents in tree nuts were not examined for their contributions to this LDL-lowering effect. Tree nuts are rich in phytosterols that displace cholesterol from intestinal micelles and reduce the pool of absorbable cholesterol. Phytosterols also exhibit LDL-lowering effects in intact foods (4).

To investigate the role of phytosterols in the LDL-lowering effect of tree nuts, we conducted a systematic review and meta-analysis of controlled interventional trials. We included trials that provided nuts or dietary advice and that examined LDL cholesterol in adults (age ≥18 years) who were free of coronary heart disease or stroke.

Two investigators (M.F., K.L.) screened potentially eligible PubMed articles, adjudicated inclusion decisions, and extracted data. We calculated mean differences between tree nut intervention and control arms that were dose-standardized to one 1-oz (28.4 g) serving/day, using inverse variance fixed-effects meta-analysis. Phytosterol dose was determined by multiplying the daily nut intake by the phytosterol content of the specific nut types supplied (4), with and without adjustment for the overall dose of nuts. Meta-regression was used to evaluate the association of phytosterol intake with LDL cholesterol.

Of 1,301 potentially eligible articles, 61 trials met eligibility criteria (42 randomized, 18 nonrandomized), with a total of 2,582 unique participants. Interventions ranged from 3 to 26 weeks, with nut and phytosterol doses ranging from 0.2 to 3.5 servings and 4.8 to 279 mg/day, respectively. Across the 61 trials, the median baseline LDL cholesterol concentration was 131 mg/dl (range: 73 to 162 mg/dl). All of the trials directly provided nuts, rather than relying only on dietary advice. Fourteen trials included advice to maintain isocaloric balance; in the remaining 47 trials, participants were provided nuts on top of a common background diet. Compliance was generally assessed using self-reported dietary recalls or direct supervision of nut consumption. For meta-regression, trials of mixed nuts (in which the phytosterol content of specific nut types could not be ascertained) were excluded.

Compared with control groups, each daily serving of tree nuts lowered LDL cholesterol (–4.8 mg/dl; 95% confidence interval: –5.5 to –4.2). Total phytosterol intake from nuts was correlated with nut dose (r = 0.84). In pooled analyses, total phytosterol dose from nuts was inversely correlated with a reduction in LDL (r = –0.60) (Figure 1A). However, this association was not independent of total nut dose: after standardization of nut dose, phytosterol content was no longer independently associated with LDL (r = –0.01; p > 0.05) (Figure 1B).

Associations of Phytosterol Intake From Nuts and Mean Difference in LDL

(A) Relation of total phytosterol intake (mg) from nuts and absolute mean difference in LDL. (B) Relation of phytosterol intake (standardized to 1 serving/day [28.4 g] of different nut types) and mean difference in LDL (standardized to 1 serving/day). Phytosterol-LDL associations were modeled using meta-regression. Total phytosterol intake was calculated by multiplying the daily nut intake dose for a given nut type from each trial by the phytosterol content of each nut type, given in Phillips et al. (4). Trials of mixed nuts were excluded. LDL = low-density lipoprotein.

Potential limitations should be considered. Compliance was often assessed by self-report, and low compliance could cause underestimation of effects. Some trials were nonrandomized; however, similar findings were seen in randomized trials (data not shown). The relative variation in phytosterol dose, accounting for total nut dose, might be too small to be clinically meaningful.

In conclusion, our analysis demonstrates that the dose of phytosterol intake from tree nuts is associated with the LDL-lowering effect, but that this relationship is driven by the total daily dose of nuts, rather than by differences in phytosterol content between types of nuts.

Footnotes

Please note: This work was supported by R01-HL085710-07. Drs. Del Gobbo and Mozaffarian have received modest ad hoc consulting fees from the Life Sciences Research Organization (LSRO) to support this study. Dr. Mozaffarian has received ad hoc honoraria from Bunge, Pollock Institute, and Quaker Oats; ad hoc consulting for Foodminds, Nutrition Impact, Amarin, AstraZeneca, and Winston and Strawn LLP; has membership in the Unilever North America Scientific Advisory Board; and chapter royalties from UpToDate. Drs. Falk, Feldman, and Lewis received payment through LSRO (<5% of gross income) to conduct a review of nuts and cardiovascular health outcomes, which was funded through a contract with the International Tree Nut Council (ITNC). No author has stock or ownership in the INTC. Funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of this paper.

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